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T-cell-targeted immunotherapy
T-cell-targetedimmunotherapy Marc Feldmann, Carl H. June, Andrew McMichael, Ravinder Maini, Elizabeth Simpson and James N. Woody
The critical component for T-cell activation, namely the T-cell receptor (TCR), which recognizes peptide epitopes bound in the cleft of major histocompatibility complex (MHC) class II molecules, has been defined in molecular terms. This has spurred the development of new approaches to the specific modulation of T-cell activity. The definition of natural cytokine antagonists has provided yet another approach to immunotherapy. A realistic appraisal of the progress to date and the prospects for these novel therapies in allergic, inflammatory and autoimmune diseases is given below.
Peptides as inhibitors The idea behind blocking peptides is that they can bind to the appropriate MHC molecule (for example, a class II molecule associated with a particular autoimmune disease) but cannot activate pathogenic T-cell responses. H. McDevitt (Stanford) has demonstrated the potential of this system in a mouse strain susceptible to experimental allergic encephalomyelitis (EAE): the co-administration of a single amino acidsubstituted homologous myelin basic protein (MBP)-derived peptide along with the encephalitogenic MBP peptide partially blocked the development of disease. However, a response to the blocking peptide could be generated in vitro so attention turned to unrelated blockers. An ovalbumin-derived peptide, OVA 329-339, successfully prevented the onset of EAE and was nonimmunogenic. In functional studies, L. Adorini (Basel) showed that the generation of immunogenicpeptide-class-ll complexes was blocked by the injection of homologous or nonhomologous peptide in complete Freund's adjuvant, dimin-
The pace of T-cell research is matched only by the speed with which fundamental advances are being developed as new therapies. This report from a recent meeting* updates developments in a number of immunointervention strategies. ishing T-cell and antibody responses. Different approaches to using peptides for immune regulation were described by S. Sharma (Redwood City, CA). One strategy was to use complexes of peptide, class II molecules and the toxin adriamycin. This complex kills T cells that bind to it in vitro. Another method involved the administration of soluble peptide-class-lI complexes in vivo: marked amelioration of mouse EAE resulted using as little as 300 ~g of peptide-I-A+ complexes. Analogous studies have been performed in experimental myasthenia gravis in Lewis rats. Even after the onset of disease the peptide-class-ll complexes are effective in vivo. These complexes can induce anergy in vitro, although whether this is the mechanism in vivo remains to be determined. All these findings are positive but to be of value in treating human diseases it may be necessary to maintain high concentrations of blocking peptide, which may have adverse effects on immunity in general. Also, peptides that block a wide range of different MHC molecules may have to be identified, as the MHC restriction elements for human diseases have yet to be defined. There is, as yet, no conclusive or direct evidence that susceptibility alleles encode restriction elements; they could influence susceptibility by shaping the T-cell repertoire. Encouragingly, for one allergen M. Gefter (La Jolla)
found that <25% of the sequence accounted for T-cell recognition on many different HLA class II alleles. This bodes well for toleranceinducing regimens.
Anti-cytokine therapy
Anti-cytokine therapy, particularly directed against interleukin 1 (IL-1) and tumour necrosis factor (TNF-cx), holds much promise. R. Thompson (Boulder, Colorado) described an IL-1 receptor antagonist; it blocks the pathological inflammatory effects of IL-1 but appears not to inhibit immune responses. In contrast, soluble IL-1 receptor (IL-IR) is immunosuppressive (S. Gillis, Seattle). The reasons for this difference are not clear. Soluble IL-1R is effective in preventing heart graft rejection in mice and in reducing arthritis and EAE in Lewis rats. An endogenously-produced soluble IL-1 receptor has been identified in synovial fluid and shown to be produced by B-cell tumours (J. Symons, Sheffield). It is closely related, structurally, to type II IL-1R but may represent a third, as yet undefined, class. A key question for therapy development is which cytokine provides the best target? In rheumatoid arthritis, TNF-o~ appears to be pivotal: anti-TNF antibodies reduce IL-1 and granulocyte-macrophage colony-stimulating factor (GMCSF) production, HLA class II expression and cell adhesion. Furthermore, there is upregulation of both membrane-bound and soluble TNF receptor (TNF-R) (F. Brennan, London). The latter may be developed as a therapeutic tool: Gillis *The meeting on 'T-cell Activation in reported that soluble TNF-R was Heath and Disease: Immunotherapy' effective in reducing pathology in was held in Oxford, UK on 21-25 adjuvant arthritis and septic shock although D. Wallach (Rehovot) September 1991.
© 1992, Elsevier Science Publishers Ltd, UK.
Immunology Today
84
Vol 13 No. 3 1992
TRENDS pointed out that soluble TNF-R may act as a carrier protein, as well as an inhibitor of TNF.
Anti-T-cell antibodies The use of anti-CD4 and/or anti-CD8 antibodies to prevent allograft rejection in mice, by depleting responding T-cell populations, was described by S. Cobbold (Cambridge). Less drastically, nondepleting anti-CD4 antibody can be used to generate what appears to be anergy to soluble and cell-bound antigens; this anergy depends on the persistence of antigen. Antibody therapy is already being applied in human diseases: a preliminary report on the use of a chimaeric antiCD4 antibody in rheumatoid arthritis claimed clinical benefit to 40% of patients (M. Sanders, Malvern, PA). The antibody was not toxic but did deplete CD4 + T cells, raising questions about long-term effects on immunocompetence, although none was detected. More attractive, at least in theory, is the prospect of 'knocking out' pathogenic T-cell clones. Encouragingly, limited TCR usage is a feature of a number of experimental autoirnmune diseases and therapy using anti-V~ antibodies has met with some success in EAE and collagen-induced arthritis. However, J.F. Bach (Paris) reported that only limited protection can be achieved in one animal model, namely insulin-dependent diabetes mellitus in nonobese diabetic (NOD) mice, by treatment with anti-V~ antibodies. This contrasts with the virtually complete protection engendered using anti-CD3 antibodies. Combined with the fact that compelling evidence for restricted TCR gene usage in human autoimmune disease is still lacking, anti-V~3 antibody therapy may not be a realistic short-term prospect, although its specificity makes it an exciting longterm one if methods are developed to help define TCR usage in pathogenic human T-cell clones. Advances in immunology Progress in selected aspects of fundamental T-cell biology were also highlighted at the meeting. One of these was the influence of superantigens on the selection of the T-cefl repertoire. Mature mouse T cells,
isolated from peripheral lymphoid organs, generally display random V(,-V~ pairing despite the fact that major deletions in the repertoire do occur: endogenous superantigens cause clonal elimination of thvmic T cells that express particular V~3 chains (R. Hodes, Bethesda). If deletion is partial, no skewing of V,,VI3 associations is found, suggesting that V~ chains play no role in the recognition of endogenous superantigens. However, when T cells from an Mls~unegative mouse, which does not delete V~6 + T cells, encounter Mist'-positive stimulators, the phenotype of the proliferating V 6 + T cells is skewed, suggesting that superantigen activation can be influenced by TCR ~xchains, Endogenous superantigens that affect T-cell repertoire selection in mice are the products of an open reading frame (orf) in the long terminal repeat of various mouse mammary turnout virus (Mtv) integrations. Orf products are type 2 glycoproteins, polymorphic at the carboxy terminus. A new V~3deletion ligand gene, Mtv-44, has been discovered (E. Simpson, London). It is likely that Mtv-44 shares close carboxy-terminal sequence homology with Mtv- 1, -3, -6, and -13, which also delete VI~3~ "1 cells. In humans, the response to exogenous superantigens is also influenced by factors additional to V~ chains (~VI. Londei, London). The majority of a panel of 20 human T-cell clones from a single individual, all expressing Vt36.7a, responded to staphylococcal enterotoxin E (SEE) and toxic shock syndrome toxin l (TSST- l), but had
distinct response patterns. Again, it is possible that V~, plays a role; thus, in both humans and mice, the hypothesis that V~ alone influences superantigen response needs modification.
Vaccination against HIV Progress in the development of an AIDS vaccine, using recombinant gp 160, was reported by R. Redfield (Washington, DC). Multiple doses of the vaccine were administered to HIV-positive volunteers. A high proportion of multiply-immunized individuals responded, as assessed bv antibody titres, and in this group CD4 + T-cell numbers were stable over the 18-month period assessed. Sera from vaccinated individuals could neutralize their own virus. Clearly, vaccination, the oldest form of immunotherapy, still has a lot to offer. Marc Feldmann is at the Chafing Cross Sunley Research (;entre, Lurgan Avenue, Hammersmith, London W6 8L W, UK; Carl H. June is at the Naval Medical Research Institute, 8901 Wisconsin Avenue, Bethesda, MD 20889-5055, USA; Andrew McMichael is at the Institute for Molecular Medicine, .]ohn Radcliffe Hospital, Headington, ()xfi)rd OX3 9DE, UK; Ravinder N. Mami is at the Kennedy Institute of Rheumatology, 6 Bute Gardens, Hammersmith, London W6 7DW, UK; Elizabeth Simpson is at the Clinical Research Centre, Transplantation Biology Section, Watford Road, Harrow HAl 3UJ, UK; and ]ames N. Woody is at Centocor Inc., 200 Great Valley Parkway, Malvern, PA 19 3~ ~, US,~.
N * The mechanism of action of cyclosporin A and FKS06
* Immunophysiology lung
* T suppressor cells revisited
* Animal models of immunodeficiency
* The immune system in lower vertebrates
* An a ~ view o f malaria vaccine d e v e l o p ~ t
Immunology Today
85
Vol. 13 No. ~ 1992
of the
The critical component for T-cell activation, namely the T-cell receptor (TCR), which recognizes peptide epitopes bound in the cleft of major histocompatibility complex (MHC) class II molecules, has been defined in molecular terms. This has spurred the development of new approaches to the specific modulation of T-cell activity. The definition of natural cytokine antagonists has provided yet another approach to immunotherapy. A realistic appraisal of the progress to date and the prospects for these novel therapies in allergic, inflammatory and autoimmune diseases is given below.
Peptides as inhibitors The idea behind blocking peptides is that they can bind to the appropriate MHC molecule (for example, a class II molecule associated with a particular autoimmune disease) but cannot activate pathogenic T-cell responses. H. McDevitt (Stanford) has demonstrated the potential of this system in a mouse strain susceptible to experimental allergic encephalomyelitis (EAE): the co-administration of a single amino acidsubstituted homologous myelin basic protein (MBP)-derived peptide along with the encephalitogenic MBP peptide partially blocked the development of disease. However, a response to the blocking peptide could be generated in vitro so attention turned to unrelated blockers. An ovalbumin-derived peptide, OVA 329-339, successfully prevented the onset of EAE and was nonimmunogenic. In functional studies, L. Adorini (Basel) showed that the generation of immunogenicpeptide-class-ll complexes was blocked by the injection of homologous or nonhomologous peptide in complete Freund's adjuvant, dimin-
The pace of T-cell research is matched only by the speed with which fundamental advances are being developed as new therapies. This report from a recent meeting* updates developments in a number of immunointervention strategies. ishing T-cell and antibody responses. Different approaches to using peptides for immune regulation were described by S. Sharma (Redwood City, CA). One strategy was to use complexes of peptide, class II molecules and the toxin adriamycin. This complex kills T cells that bind to it in vitro. Another method involved the administration of soluble peptide-class-lI complexes in vivo: marked amelioration of mouse EAE resulted using as little as 300 ~g of peptide-I-A+ complexes. Analogous studies have been performed in experimental myasthenia gravis in Lewis rats. Even after the onset of disease the peptide-class-ll complexes are effective in vivo. These complexes can induce anergy in vitro, although whether this is the mechanism in vivo remains to be determined. All these findings are positive but to be of value in treating human diseases it may be necessary to maintain high concentrations of blocking peptide, which may have adverse effects on immunity in general. Also, peptides that block a wide range of different MHC molecules may have to be identified, as the MHC restriction elements for human diseases have yet to be defined. There is, as yet, no conclusive or direct evidence that susceptibility alleles encode restriction elements; they could influence susceptibility by shaping the T-cell repertoire. Encouragingly, for one allergen M. Gefter (La Jolla)
found that <25% of the sequence accounted for T-cell recognition on many different HLA class II alleles. This bodes well for toleranceinducing regimens.
Anti-cytokine therapy
Anti-cytokine therapy, particularly directed against interleukin 1 (IL-1) and tumour necrosis factor (TNF-cx), holds much promise. R. Thompson (Boulder, Colorado) described an IL-1 receptor antagonist; it blocks the pathological inflammatory effects of IL-1 but appears not to inhibit immune responses. In contrast, soluble IL-1 receptor (IL-IR) is immunosuppressive (S. Gillis, Seattle). The reasons for this difference are not clear. Soluble IL-1R is effective in preventing heart graft rejection in mice and in reducing arthritis and EAE in Lewis rats. An endogenously-produced soluble IL-1 receptor has been identified in synovial fluid and shown to be produced by B-cell tumours (J. Symons, Sheffield). It is closely related, structurally, to type II IL-1R but may represent a third, as yet undefined, class. A key question for therapy development is which cytokine provides the best target? In rheumatoid arthritis, TNF-o~ appears to be pivotal: anti-TNF antibodies reduce IL-1 and granulocyte-macrophage colony-stimulating factor (GMCSF) production, HLA class II expression and cell adhesion. Furthermore, there is upregulation of both membrane-bound and soluble TNF receptor (TNF-R) (F. Brennan, London). The latter may be developed as a therapeutic tool: Gillis *The meeting on 'T-cell Activation in reported that soluble TNF-R was Heath and Disease: Immunotherapy' effective in reducing pathology in was held in Oxford, UK on 21-25 adjuvant arthritis and septic shock although D. Wallach (Rehovot) September 1991.
© 1992, Elsevier Science Publishers Ltd, UK.
Immunology Today
84
Vol 13 No. 3 1992
TRENDS pointed out that soluble TNF-R may act as a carrier protein, as well as an inhibitor of TNF.
Anti-T-cell antibodies The use of anti-CD4 and/or anti-CD8 antibodies to prevent allograft rejection in mice, by depleting responding T-cell populations, was described by S. Cobbold (Cambridge). Less drastically, nondepleting anti-CD4 antibody can be used to generate what appears to be anergy to soluble and cell-bound antigens; this anergy depends on the persistence of antigen. Antibody therapy is already being applied in human diseases: a preliminary report on the use of a chimaeric antiCD4 antibody in rheumatoid arthritis claimed clinical benefit to 40% of patients (M. Sanders, Malvern, PA). The antibody was not toxic but did deplete CD4 + T cells, raising questions about long-term effects on immunocompetence, although none was detected. More attractive, at least in theory, is the prospect of 'knocking out' pathogenic T-cell clones. Encouragingly, limited TCR usage is a feature of a number of experimental autoirnmune diseases and therapy using anti-V~ antibodies has met with some success in EAE and collagen-induced arthritis. However, J.F. Bach (Paris) reported that only limited protection can be achieved in one animal model, namely insulin-dependent diabetes mellitus in nonobese diabetic (NOD) mice, by treatment with anti-V~ antibodies. This contrasts with the virtually complete protection engendered using anti-CD3 antibodies. Combined with the fact that compelling evidence for restricted TCR gene usage in human autoimmune disease is still lacking, anti-V~3 antibody therapy may not be a realistic short-term prospect, although its specificity makes it an exciting longterm one if methods are developed to help define TCR usage in pathogenic human T-cell clones. Advances in immunology Progress in selected aspects of fundamental T-cell biology were also highlighted at the meeting. One of these was the influence of superantigens on the selection of the T-cefl repertoire. Mature mouse T cells,
isolated from peripheral lymphoid organs, generally display random V(,-V~ pairing despite the fact that major deletions in the repertoire do occur: endogenous superantigens cause clonal elimination of thvmic T cells that express particular V~3 chains (R. Hodes, Bethesda). If deletion is partial, no skewing of V,,VI3 associations is found, suggesting that V~ chains play no role in the recognition of endogenous superantigens. However, when T cells from an Mls~unegative mouse, which does not delete V~6 + T cells, encounter Mist'-positive stimulators, the phenotype of the proliferating V 6 + T cells is skewed, suggesting that superantigen activation can be influenced by TCR ~xchains, Endogenous superantigens that affect T-cell repertoire selection in mice are the products of an open reading frame (orf) in the long terminal repeat of various mouse mammary turnout virus (Mtv) integrations. Orf products are type 2 glycoproteins, polymorphic at the carboxy terminus. A new V~3deletion ligand gene, Mtv-44, has been discovered (E. Simpson, London). It is likely that Mtv-44 shares close carboxy-terminal sequence homology with Mtv- 1, -3, -6, and -13, which also delete VI~3~ "1 cells. In humans, the response to exogenous superantigens is also influenced by factors additional to V~ chains (~VI. Londei, London). The majority of a panel of 20 human T-cell clones from a single individual, all expressing Vt36.7a, responded to staphylococcal enterotoxin E (SEE) and toxic shock syndrome toxin l (TSST- l), but had
distinct response patterns. Again, it is possible that V~, plays a role; thus, in both humans and mice, the hypothesis that V~ alone influences superantigen response needs modification.
Vaccination against HIV Progress in the development of an AIDS vaccine, using recombinant gp 160, was reported by R. Redfield (Washington, DC). Multiple doses of the vaccine were administered to HIV-positive volunteers. A high proportion of multiply-immunized individuals responded, as assessed bv antibody titres, and in this group CD4 + T-cell numbers were stable over the 18-month period assessed. Sera from vaccinated individuals could neutralize their own virus. Clearly, vaccination, the oldest form of immunotherapy, still has a lot to offer. Marc Feldmann is at the Chafing Cross Sunley Research (;entre, Lurgan Avenue, Hammersmith, London W6 8L W, UK; Carl H. June is at the Naval Medical Research Institute, 8901 Wisconsin Avenue, Bethesda, MD 20889-5055, USA; Andrew McMichael is at the Institute for Molecular Medicine, .]ohn Radcliffe Hospital, Headington, ()xfi)rd OX3 9DE, UK; Ravinder N. Mami is at the Kennedy Institute of Rheumatology, 6 Bute Gardens, Hammersmith, London W6 7DW, UK; Elizabeth Simpson is at the Clinical Research Centre, Transplantation Biology Section, Watford Road, Harrow HAl 3UJ, UK; and ]ames N. Woody is at Centocor Inc., 200 Great Valley Parkway, Malvern, PA 19 3~ ~, US,~.
N * The mechanism of action of cyclosporin A and FKS06
* Immunophysiology lung
* T suppressor cells revisited
* Animal models of immunodeficiency
* The immune system in lower vertebrates
* An a ~ view o f malaria vaccine d e v e l o p ~ t
Immunology Today
85
Vol. 13 No. ~ 1992
of the